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  • Review Article
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Ion channel structure

The structure and function of glutamate receptor ion channels

Nature Reviews Neuroscience volume 3, pages 91–101 (2002)Cite this article

Key Points

  • New insights into the structures of glutamate receptor ion channels (iGluRs), combined with functional and biochemical data, can help us to understand how agonist binding triggers their activation and subsequent desensitization. Studies of related channels also provide valuable insights into the molecular basis of ion selectivity and transport.

  • iGluRs are important for fast excitatory neural signalling and for synaptic plasticity. They are constructed from subunits that include an amino-terminal domain (NTD), a ligand-binding domain (S1S2), three transmembrane domains, a P-loop domain and a carboxy-terminal domain.

  • The ligand-binding domain, S1S2, can be expressed and studied in isolation. It consists of two lobes that form a cleft, which is open at rest. When it binds agonist, the cleft closes around the ligand through a conformational change involving the formation of hydrogen bonds between the agonist and S1S2. The mechanism of closure involves an open⇔closed equilibrium for the ligand-binding domain. The balance of equilibrium shifts from the open to the closed state when it interacts with agonist.

  • The ligand-binding site seems to possess several 'subsites' that participate in ligand binding. Not all of these subsites need to be occupied for agonist binding, providing the flexibility to bind various agents. Vibrational spectroscopy shows that electronegative ligand moieties interact with electronegative groups in the binding site.

  • It is not clear how the receptor subunits combine to form an ion channel. It is proposed that tetrameric channels form as a 'dimer of dimers', with initial dimerization being mediated by the NTDs, and the second dimerization of dimers requiring compatibility between the S2 and transmembrane domains.

  • Current models of channel activation and desensitization involve cleft closure in each subunit, pulling the transmembrane domains of the subunit away from the pore axis, and thus opening the channel. The channel then closes by slippage between subunits.

  • Glutamate receptors are permeable to both K+ and Na+, and in some cases to divalent cations. It seems likely that the channel opens wide enough to allow ions to pass through with their hydration shells. This contrasts with the K+ channels, in which ions are dehydrated at the entrance to the channel.

  • Many questions remain to be answered about the ligand binding, activation, ion permeation and desensitization of iGluRs. The packing and symmetry of the P-loop sequence are unclear, as are the assembly interactions of the subunits. As these details become better understood, they will help us to understand the kinetics and selectivity of glutamate-gated channels.

Abstract

As in the case of many ligand-gated ion channels, the biochemical and electrophysiological properties of the ionotropic glutamate receptors have been studied extensively. Nevertheless, we still do not understand the molecular mechanisms that harness the free energy of agonist binding, first to drive channel opening, and then to allow the channel to close (desensitize) even though agonist remains bound. Recent crystallographic analyses of the ligand-binding domains of these receptors have identified conformational changes associated with agonist binding, yielding a working hypothesis of channel function. This opens the way to determining how the domains and subunits are assembled into an oligomeric channel, how the domains are connected, how the channel is formed, and where it is located relative to the ligand-binding domains, all of which govern the processes of channel activation and desensitization.

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Figure 1: The modular nature of iGluR subunits.
Figure 2: Cleft closure mirrors extent of activation.
Figure 3: Ligand binding to the S1S2 domain.
Figure 4: Conformational transitions in the S1S2 domain.
Figure 5: Assembly of the iGluR.
Figure 6: A model for iGluR activation and desensitization4,5.

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Acknowledgements

This review is dedicated to the memory of Don C. Wiley, a great scientist, mentor and friend.

Author information

Authors and Affiliations

  1. Ion Channel Structure Research Group, Max Planck Institute for Medical Research, Jahnstrasse 29, Heidelberg, 69120, Germany

    Dean R. Madden

  2. Department of Biochemistry, Dartmouth Medical School, Hanover, 03755, New Hampshire, USA

    Dean R. Madden

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DATABASES

LocusLink

δ1

δ2

GluR1

GluR2

GluR3

GluR4

GluR5

GluR6

GluR7

KA1

KA2

NR1

NR2

NR3

 Protein Data Bank

1BL8: potassium channel (KcsA)

1EWK: mGluR subtype 1, complex with glutamate

1FTJ: GluR2 S1S2J, complex with glutamate

1FTK: GluR2 S1S2I, complex with kainate

1FTL: GluR2 S1S2J, complex with DNQX

1FTM: GluR2 S1S2J, complex with AMPA

1FTO: GluR2 S1S2J, apo state

1FW0: GluR2 S1S2J, complex with kainate

1IIW: GluR0 ligand-binding core, apo state

FURTHER INFORMATION

AMPA receptors

ion channels

NMDA receptors 

Families of Transport Proteins

Ion Channel Structure Research Group

Ligand-Gated Ion Channel Database

The Ion Channel Web Page

Glossary

ALLOSTERIC

A term originally used to describe enzymes that have two or more receptor sites, one of which (the active site) binds the principal substrate, whereas the other(s) bind(s) effector molecules that can influence its biological activity. More generally, it is used to describe the indirect coupling of distinct sites within a protein, mediated by conformational changes.

P-LOOP SEQUENCE

A conserved structural motif found in many different ion channels that constitutes part of the channel pore.

PDZ DOMAIN

A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. They can bind to the carboxyl termini of proteins or can form dimers with other PDZ domains. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD95, Discs large, zona occludens 1).

STOPPED-FLOW FLUORESCENCE STUDIES

The properties of a fluorophore are dependent on its chemical environment, and can therefore be influenced by molecular interactions or conformational changes. In stopped-flow experiments, interacting molecules are rapidly mixed in a flow cell, and the temporal evolution of their fluorescence signals is monitored to determine the kinetics of the interaction.

LURCHER MUTATION

A spontaneous gain-of-function mutation in the δ2 glutamate receptor gene of mice that causes neuronal cell death, leading to loss of motor control in heterozygotes and to early postnatal mortality in homozygotes.

INFRARED SPECTROSCOPY

Many interatomic molecular vibrations show energy transitions that lead to the absorption of photons at characteristic frequencies in the infrared range. The energy transitions, and therefore the associated infrared absorption spectra, are highly sensitive to the stereochemical environment of the functional group(s) involved.

ELECTRON PARAMAGNETIC RESONANCE SPECTROSCOPY

When an atom with an unpaired electron is placed in a magnetic field, the spin of the unpaired electron can align, either in the same direction as the field or in the opposite direction. Electron paramagnetic resonance (EPR) spectroscopy is used to measure the absorption of microwave radiation that accompanies the transition between these two states.

EC50

The concentration of agonist that evokes a half-maximal response.

INHIBITION CONSTANT

A measure of affinity, determined by the displacement of a labelled reporter ligand.

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Madden, D. The structure and function of glutamate receptor ion channels. Nat Rev Neurosci 3, 91–101 (2002). https://doi.org/10.1038/nrn725

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